Aminoalkyl ethers of pyridyl alkylene aryl compounds



Patented Sept. 4, 1951 AMINOALKYL ETHERS OF PYRIDYL ALKYLENE ARYL COMPOUNDS Domenick Papa, Brooklyn, N. Y., and Nathan Sperber, Bloomfield, N. J assignors to Schering Corporation, Bloomfield, N. 1., a corporation of New Jersey No Drawing. Application August 30, 1948, Serial No. 46,923

9 Claims. (01. 260-2943?) The present invention relates to anew group 01'. compounds of interesting and important physiological action. More specifically, the invention relates to nuclear substituted amino ethers of pyridyl substituted benzenes having valuable therapeutic properties, particularly antihistaminic activity.

The compound of the present invention may be represented by the general formula [R --XR] OR" wherein R is a pyridyl, R is a benzene ring, X is abivalent aliphatic'hydrocarbon group of 1 to 3 carbon atoms and R" is a dialkylaminoalkyl,

morpholinoalkyl, piperidinoalkyl or imidazolinylalkyl radical, R being attached to one of the rings R and R. The rings R and R may be substituted by lower alkyl, lower alkoxy and halogen groups.

In general, the compounds of the present invention may be prepared by the reaction of dialkylamino-, morpholino-, piperidinoor imidazolinyl-alkyl halides with the appropriate pyridyl substituted benzene wherein either the benzene or pyridine ring has a hydroxyl group. For example, by reacting p-hydroxy-a-stilbazole in an inert organic solvent, such as toluene, with sodamide and p-dimethylaminoethyl chloride, there is obtained the I-[p-(p-dimethylaminoethoxy)phenyll 2(0. pyridyl) ethylene. The

amino ether is purified by solution in hydrochloric acid which removes neutral and acidic products and subsequent distillation of the oil obtained from the alkaline solution. In place of sodamide, sodium metal may be used as condensing agent. Other solvents such as benzene and xylene may be used in place of toluene. The following formulas illustrate the types of compounds which are within the scope of the inven- \N GHQ The following examples are illustrative of the principles of the invention:

EXAMPLE I V 1 [p- (p-dz'methylaminoethoxy) phenyll -2- (a-pyridyl) ethylene To cc. of liquidammonia, there is added 2 g. of sodium and after the sodamide has formed, the ammonia is replaced by 150 cc. of dry xylene. To the xylene suspension,there is added 11 g. of p-hydroxy-a-stilbazole. After heating the mixture for one hour on the steam bath, 15 g. of fl-N,N-dimethylaminoethyl chloride is added and the reaction is heated for an additional 10-15 hours. The excess sodamide is decomposed with water, and the organic layer isseparated, dried and vacuum concentrated. The amino ether is distilled, B. P. 190-195 C./1.0 mm.; M. P. '70- 71 C.

EXAMPLE l1 4- [0- (fl-dz'methyl aminoethoxy) -B-phenethyll pyridine To a suspension of sodamide (from 3 g. sodium) in 200 cc. xylene, there is added 20g. of y-(o-hydroxy-p-phenethyl) pyridine and after one hour of heating on the steam bath, 20 g. of fl-N,N-dimethylaminoethyl chloride is added. The reaction is stirred and heated on the steam bath for an additional 10-15 hours. The excess sodamide is decomposed with water and the amino ether is isolated as described in the previous example. It distills at -164 C./l.0 mm.

EXAMPLEIII 1n- (fi-dz'methylarhinoethoscy) phenyl- 2- py'rid'yl) methane zene layeris separated, dried over sodium sulfate,

filtered and the solvent removed under vacuum. The residueis dissolvedin 400 ccnof-glacialacetic acid; and, to the stirred solution,there is added 20 g. of zinc dust. The mixture is heated on the steam bath for '7 hours. The zinc salts are filtered off, the filtrate is vacuum concentrated and the residue made alkaline withdilute sodium hydroxide. The oil which separated is ether extracted, the ether layer-:is dried oversodium sulfate, filtered and concentrated. The p-methoxyphenyl-(2-pyridyl)rnethane boils .at 135-1I0" C./ 1.0 mm.

The p-hydroxyphenyl-(Z-pyridyllmethane is obtained from the methoxy compound by demethylation with hydrobromic and acetic acid. It distills at 172-176".C./0.5 mm.; M. P. "12955.- 130.5 C.

The amino ether is madeby alkylation with 5-.

dimethylaminoethylchloride as describedumthei previous examples, B. .P. 148-15? 0M2 mm.

. methane The o-hydroxyphenyle2- pynidylmethane'ispre- 0- (,B-dzmethylaminoethomy) phenyl- ZTyTid /ZY pared as described for the corresponding para compound of Example III-using o-methoxvbenzaldehyde. The :amino :ether adistills at .1160-164" C./ 1.5 mm.

EEXAMPIJE V "The "intermediate, 2-.(p-hydroxyphenyl) pyridine .is i-preDa-red ,from- .2-(p-methoxyphenyllp3 :ridine (Haworth, -J. C. S. ".359.-'(l940)) by demethylation with hydrobromic and :acetic lac-ids,

The amino ether .is made by .alkylation with .5- --dimethy-laminoethyl chloride as described in the :previousexamplesM. P.:52;5-+53.5' C.

2-[0-(5 dimetirylaminoethomy)phenyllpyridine i2-i(.o-=hydroxyphenyl);pyridine is prepared according to the procedure in J. Org. Chem. 11, 748 (19.46) The amino ether is made by alkylation 1 with ;N,'N-dimethylaminoethy1 chloride as described in the previous examples, B. P. 165-168" The intermediate, m-rhydroxy-a-stilbazole, -is

. prepared according to-J. Org-Chem. 10,.21 v(1945) M. P. 136.8-13'7.2 C.

The amino ether is -m-ade by alkylation with p-N,N-dimethylaminoethylchloride -as described in the previouszexamples,:BJP. 182-l86 C./1 mm.

. pyridy'l) ethane The intermediate, l-(o-hydroxyphenyb-l-(2- pyridyl) '-ethane is .made by condensing .picolinic acid with o-methoxyacetophenone .in accordance with the procedure outlined :in Example 111. The

1 pyridyl-l-phenylethanol, on treatment with 'thionyI chloridetand subsequent reduction with zinc dust, yields the l-(o-methoxyphenyl)-1-.(2-

:pyridyl) ethane. Demethylation .with hydrobrozmic acid yields the .hydroxy compound which is 1-10-1 dimth zaminoemowy) nenyzi 1-0- 4 converted into the ether as described in the pre- ,vious examples.

EXAIVIPLE IX il-[o (,s-dimethylaminoethoxy)-phenyl] 1-(zpyridyl) Pro ane "The requisite intermediate is obtained by alkylating .the .o-hydroxyphenyl-(Z-pyridyl) methlane of ExampleIV with ethyl bromide and sodadescribed in Example III is alky'lated with fpi-"( i Diperidino)ethyl chloride in accordance 'wi'th the' directions of the previous example. The compound so obtained is pur'i'fied' by solution in acid and subsequent distillation of the oil obtained from the acid solution after treatment with gaseous ammonia.

The :compounds 10f the invention may :be "used .asasuch or initheformiof theirssaltswith inorganic and organic acids, particularly-the hydrohal-ide salts, suchtas the hydrochloride;

We claim: .1. Compounds of the :group consisting-of bases of the general formula fIR- x-sri OR V "wherein R. isra pyridyl-ring R is .a benzene ring, .X is ca bivalent aliphatic hydrocarbon group .of .1 to v3 .carbon :atoms, .R," is selected :from-the group 'consistingb-f .dialkylaminoalk yl and ,piperidinoalkyl radicals, and .OR'" attached .to .one

of the ringsR and :R.,and-'the.acid.salts thereof. 2. :Compounds :of the general. formula wherein-Bis a ,pyridine-ring,.R' is a'benzene ring, X is a bivalent .aliphatichydrocar'bon group .of 1 to 3 carbon atoms, .a-ndlR" is a .dialkylaminoalkyl group. I

3. Compounds is CH2.

'4. Compounds as defined in claim '2 wherein)! as defined in claim 2 wherein X .5. A-LoJmdimethylaminorthoxy) .33 phenethyl] pyridine. I

6. p- (p-dimethylaminoethoxy) phenyl-(Z pyridyll'methane.

'7. o-(fi-dimethylaminoethoxy)phenyl-(2 pyridyl). methane.

8. 1-[o-(fl-dimethylaminoethoxy) phenyll 1- (Z-pyridyl) ethane.

9. p [B (4 piperidino') ethoxylpheny-l-(Z-pyridyl) methane. I

DOMENICK NATHAN SPERBER.

REFERENCES CITED The following references are of record in the file of this patent:

Hartman: California Medicine BG, 24s (1947). Huttrer: Enzymologia 12,327 (1948). 

1. COMPOUNDS OF THE GROUP CONSISTING OF BASES OF THE GENERAL FORMULA 